Using a powerful and uniquely well characterized set of Hispanic individuals selected for having only Amerindian-European admixture, we will perform a genome-wide association scan to identify novel systemic lupus erythematosus genes in Native Americans. Hispanics are an expanding minority in the US and are particulariy susceptible to develop severe and early onset lupus. Indeed, recent evidence suggests that ncreased risk for lupus correlates with the proportion of Amerindian genome in patients. By selecting individuals with early age of onset, probands from multiplex families and individuals originating from high Amerindian admixture countries, we will maximize the probabilities of identifying Amerindian genes contributing to disease susceptibility. The aims of Project 3 are to 1: Perform a genome-wide association scan with 1,800,000 markers in 1,200 Hispanic cases and 600 controls in addition to neariy 700 out-of-study controls as a first stage towards the identification of genes of Amerindian origin for lupus; 2: Replicate the putative genetic associations in independent Hispanic cases and controls in a second stage analysis; 3: Use trans-racial mapping to define the origin and evolutionary history of the disease risk alleles and haplotypes as well as the common or divergent susceptibility genes across populations; and 4: Perform re-sequencing and gene expression analysis of novel and convincingly associated genes to identify all potential functional variation. In conjunction with Project 1, a much more detailed analysis of the MHC region will be performed so that its contribution, whether due to HLA-DRB1 genes or other genes, is defined. We expect to identify major and novel susceptibility genes for lupus and through focused re-sequencing, to identify the risk mutations for the genes with the major effects on disease susceptibility. RELEVANCE (See instructions): Through the identification of the risk genes for Hispanics. we will be able to study their relevance in the eariy development of the disease as well as with severity of the clinical presentation. We expect to be able to find associations between these genes and outcome measures. Results of this study should facilitate the search for novel drug targets that will lead to the possibility of improved therapeutics.